Bronchial asthma is a pathological condition where the airway is constricted by airway contraction or inflammation, which causes paroxysmal coughing, stridor, and dyspnea. Therapeutic agents for bronchial asthma include inhaled steroids, which have potent anti-inflammatory effects, β stimulants or theophyllines which are bronchodilating agents, and agents which inhibit the activity of chemical mediators, etc.
Histamines, leukotrienes, prostaglandins, and the like are known as chemical mediators which are released from mast cells or inflammatory cells involved in bronchial asthma. Among leukotrienes (LTs), cysteinyl leukotrienes (hereinafter, referred to as “cysLTs”) represented by LTC4, LTD4 and LTE4 have an approximately 1,000-fold stronger airway contractile effect as compared to histamine. Moreover, cysLTs promote induction of airway inflammation, typically by inflammatory cell infiltration, increased airway hypersensitivity and mucus secretion in the airway, by which they are deeply involved in the underlying pathological condition of bronchial asthma.
CysLTs are physiologically active substances in vivo which are 5-lipoxygenase metabolites of arachidonic acid. There are at least two different types of receptors for cysLTs, wherein cysLT1 receptor and cysLT2 receptor have been cloned to date (Nature, 399, 789-793, 1999, J. Biol., Chem., 275, 30531-30536, 2000). CysLT1 receptor is expressed primarily in airway smooth muscle, and deeply relates to the onset of bronchial asthma (Am. J. Respir. Crit. CareMed., 163, 226-233, 2001). Meanwhile, it has been reported that cysLT2 receptor adopts LTC4, LTD4, and LTE4 as a ligand, similar to the cysLT1 receptor, and is expressed in bronchial smooth muscle (J. Biol. Chem., 275, 30531-30536, 2000, Am. J. Respir. Crit. CareMed., 164, 2098-2101, 2001).
Pranlukast hydrate, Montelukast sodium and Zafirlukast are currently commercially available leukotriene receptor antagonists, and they are used as an oral drug for treating bronchial asthma and/or an oral drug for treating allergic rhinitis.

However, it is known that these leukotriene receptor antagonists are more effective for mild or moderate bronchial asthma than for severe ones. It is also known that there exist some non-responders whom the pharmaceutical agent does not have sufficient effects in mild or moderate bronchial asthma. Accordingly, there has been a demand for agents having a higher therapeutic activity than the existing agents.
One of the means for accomplishing the object is to enhance a leukotriene receptor antagonistic activity of the agents. The currently commercially available three compounds are all cysLT1 antagonists. As approaches to potentiate the receptor antagonistic activity, a method of further enhancing a cysLT1 antagonistic activity and a method of constructing a combination of cysLT1 antagonistic activity and cysLT2 antagonistic activity are devised.
Meanwhile, antiasthmatic drugs are required to be medicated on a regular basis and therefore oral preparations are preferred which are convenient for taking medicine. Among oral preparations, drugs with less dosing frequencies are preferred for convenience of medication. Namely, an oral anti-asthma drug is preferred having a long-term activity. With regard to development of oral preparations, it is very important to improve the duration of drug efficacy.
However, particularly in oral preparations, a compound that is of interest per se may be labile; may exhibit poor delivery to the target organ; may exhibit early metabolism and excretion even though an antagonistic activity of the compound is potent. For these reasons, it is not easy to obtain a compound having long-lasting potent effects.
Patent Document 1 describes that a compound represented by the general formula (A):
wherein R1A and R2A each independently represent an acidic group which may be protected, DA and EA each independently represent a bond or a spacer which has a main chain having 1 to 8 atoms, R3A represents a substituent, ring AA represents a cyclic group which may further have substituent(s), ring BA represents a cyclic group which may further have substituent(s), YA and ZA each independently represent a carbon atom or a nitrogen atom,represents a single bond or a double bond, wherein when YA and/or ZA represents a nitrogen atom, the bond represents a single bond, has cysLT2 receptor antagonistic effects. However, there is no disclosure or suggestion of which ring specifically contributes to the duration of drug efficacy, even though a variety of ring-fused compounds are disclosed therein.
Patent Document 2 describes that a compound shown by the general formula (B)
wherein R11B and R12B each independently represent a substituent, two groups selected from R51B, R52B and R53B each independently represent a group having an acidic group which may be protected, the other one of R51B, R52B and R53B represents a hydrogen atom or a substituent, R3B represents
wherein VB and WB each independently represent a bond or a spacer which has a main chain having 1 to 8 atoms, ring AB and ring BB each independently represent a cyclic group which may have substituent(s) or the like, mB represents 0 or an integer of 1 to 4, nB represents 0 or an integer of 1 to 2, pB represents 0 or 1,represents a single bond or a double bond, provided that a sum of mB and pB is an integer less than or equal to 4 (explanation of the groups excerpted a necessary part), has potent leukotrien receptor antagonistic effects, in combination with an excellent oral activity. However, even though various kinds of substituents are described in the afore-referenced Patent Document, there is no disclosure or suggestion of effects that may be obtained based on the kind of substituents and/or substitution positions. Particularly, Patent Document 2 is completely silent on a scheme to improve the duration of drug efficacy with retaining a potent oral activity. Furthermore, in Patent Document 2, the exemplified compound wherein VB represents a triple bond is only 4-(1-(carboxymethyl)-7-{[2-hydroxy-4-(4-phenoxybutoxy)phenyl]ethynyl}-1H-indol-3-yl)butanoic acid described in Example 101.
Furthermore, in Japanese Unexamined Published Patent Application No. 2010-168359 (hereinafter, sometimes abbreviated to Patent Document 3), compound I, compound II, and compound III are described in Example 14(2), 9, and 14(3), respectively.